More than 10 years after the enactment of FDC Act § 505(q), titled “Petitions and Civil Actions Regarding Approval of Certain Applications,” interest in citizen petitions remains high. Each year we see several analyses of the effects of citizen petitions on generic competition, as well as recommendations to improve the petitioning process (see here, here, here, and here).  Another annual occurrence is the publication of FDA’s Report to Congress on 505(q) Citizen Petitions.  FDA recently released this report – the Ninth Annual Report to Congress on Delays in Approvals of Applications Related to Citizen Petitions and Petitions for Stay of Agency Action for Fiscal Year 2016.  The Report, which is required by FDC Act § 505(q)(3), gives us the skinny on FDA’s experience during Fiscal Year 2016 (“FY 2016”) with citizen petitions subject to FDC Act § 505(q).  While the Report provides updated numbers for FY 2016 and largely repeats both FDA’s concerns about petitioning expressed in previous reports (see our previous posts here, here, here, here, here, here, here, and here) and the trends the Agency has been seeing in petitioning, FDA appears to be adopting a new tone and an action plan to address petitioning concerns.

By way of background, FDC Act § 505(q) was added to the law by the 2007 FDA Amendments Act (“FDAAA”) and is intended to prevent the citizen petition process from being used to delay approval of pending ANDAs and 505(b)(2) applications.  The law was amended by Section 301 of Pub. L. No. 110-316 (2008), and again by Section 1135 of the 2012 FDA Safety and Innovation Act (“FDASIA”).  Among other things, FDASIA changed the original 180-day response deadline to 150 days, and made the law applicable to citizen petitions concerning biosimilar applications submitted to FDA pursuant to PHS Act § 351(k). In June 2011, FDA issued final guidance on FDC Act § 505(q).  That guidance was revised in November 2014 to account for changes made to the law by FDASIA.  In January 2012, FDA issued proposed regulations to amend the Agency’s citizen petition regulations to implement changes made to the law by Section 505(q). FDA issued a final rule in November 2016.

Under FDC Act § 505(q), FDA shall not delay approval of a pending ANDA, 505(b)(2) application, or 351(k) biosimilar application as a result of a citizen petition submitted to the Agency pursuant to 21 C.F.R. § 10.30 (citizen petition) or § 10.35 (petition for stay of action), unless FDA “determines, upon reviewing the petition, that a delay is necessary to protect the public health.” FDA is required to “take final agency action on a petition not later than 150 days after the date on which the petition is submitted.”  FDA may not extend the 150-day period “for any reason,” including consent of the petitioner.  Although the statute provides that FDA may summarily deny a petition submitted with the primary purpose of delaying ANDA, 505(b)(2) application, or 351(k) biosimilar approval, the Agency has never done so.

FDC Act § 505(q)(3) requires that each Report to Congress specify: “(A) the number of applications that were approved during the preceding 12-month period; (B) the number of such applications whose effective dates were delayed by petitions . . . during such period; (C) the number of days by which such applications were so delayed; and (D) the number of such petitions that were submitted during such period.”  FDA says in its Ninth Annual Report to Congress that:

During the FY 2016 reporting period, the Agency approved 651 ANDAs, 51 505(b)(2) applications, and 3 biosimilar biological product applications. No approvals for biosimilar biological product applications or ANDAs were delayed because of a 505(q) petition in this reporting period.  The approval of one 505(b)(2) application was delayed because of one 505(q) petition.  During FY 2016, FDA received 19 505(q) petitions.

The delayed 505(b)(2) approval was delayed by 28 days. “FDA was concerned that if it approved the 505(b)(2) application before resolving the issues raised in the petitions and later concluded that one or more of the arguments against approval were meritorious, then the presence on the market of a drug product that did not meet the requirements for approval could negatively affect public health,” says FDA in the report (in what is now boilerplate language).  FDA does not identify by name or application number the particular approval delayed.

As to the number of 505(q) citizen petitions submitted in FY 2016, the Report says that the Agency received 19 petitions. From FY 2008 through FY 2016, FDA received a total of 194 505(q) petitions, and responded to all but 14 of them within the statutory timeframe (i.e., 180 days or 150 days).  That’s a pretty good track record; however, in many cases FDA merely denies a petition without substantive comment (see, e.g., here).  According to FDA, “[t]here is no evidence that in enacting section 505(q) of the FD&C Act, Congress intended to bypass the application review process or to lessen the procedural rights of an ANDA or NDA applicant by requiring that the Agency make decisions that constitute final Agency action regarding the approvability of certain aspects of pending applications on a piecemeal basis outside of the process established under the FD&C Act and FDA regulations.”

The outcomes of FDA’s 182 petition responses from FY 2008 through FY 2016 are shown in a table included in the report. Approximately 70% (127 petitions) of the 182 petition decisions have been denials, while another 23% (42 petitions) have been denied in part and granted in part.  Only about 4% (8 petitions) have been granted.  The remaining 5 petitions (3%) were voluntarily withdrawn by the petitioner.

As to 505(q) petitioning trends and FDA concerns, the Agency continues a trend of paring down comments that appeared in previous reports. That being said, FDA’s bottom line in the FY 2016 Report differs in tone from the bottom line in the Agency’s FY 2015 Report.  Here’s what the FY 2015 Report said:

The Agency continues to be concerned that section 505(q) may not be discouraging the submission of petitions that are intended primarily to delay the approval of competing drug products and do not raise valid scientific issues. The statute requires FDA to prioritize these petitions above other matters, such as safety petitions, that do raise important public health concerns. As a result, FDA remains concerned about the resources required to respond to 505(q) petitions within the 150-day deadline at the expense of completing the other work of the Agency.

Now compare that to the FY 2016 Report:

The Agency continues to be concerned that section 505(q) allows the submission of petitions that are intended primarily to delay the approval of competing drug products and do not raise valid scientific concerns. The FDA statute requires FDA to prioritize these petitions above other matters, such as safety petitions, that do raise important public health concerns.  The Agency remains concerned about the resources required to respond to 505(q) petitions within the 150-day deadline at the expense of completing the other work of the Agency, when these petitions are not based on public health concerns.  Accordingly, as part of the Drug Competition Action Plan, FDA is reviewing what actions can be taken to address these issues.

FDA Commissioner Dr. Scott Gottlieb announced the Agency’s Drug Competition Action Plan (“DCAP”) in Spring 2017 (here).  The intent of the DCAP is to encourage generic drug development and competition.  Since the creation of the DCAP, FDA has taken several steps to implement that plan, including holding a public meeting in July 2017 and issuing REMS guidance earlier this week (here).   Given FDA’s statement that the Agency is reviewing what actions can be taken under the DCAP to address citizen petition concerns, new citizen petition initiatives appear to be on the horizon.

The American Conference Institute (“ACI”), together with the Council for Responsible Nutrition, are sponsoring ACI’s 6th Annual Legal, Regulatory, and Compliance Forum on Dietary Supplements. The conference is scheduled to take place in Ney York, New York from June 18-20, 2018.

This “must-attend” event for legal, regulatory, and compliance stakeholders in the dietary supplement industry will not only provide “state of the union updates,” but will also allow for the opportunity to discuss and assess the politics and policy shaping the industry’s current political, legislative, and regulatory atmosphere. Conference speakers will provide their insights into the most pressing topics affecting the space.  In addition, FDA’s Robert Durkin, Deputy Director, Office of Dietary Supplements Programs CFSAN, is scheduled to give a keynote address.  Hyman, Phelps & McNamara, P.C.’s Riëtte van Laack will be speaking at a session titled “Unraveling the Complexities of FSMA Regulation.”

FDA Law Blog is a conference media partner. As such, we can offer our readers a special 15% discount. The discount code is: P15-999-FDAB18. You can access the conference brochure and sign up for the event here. We look forward to seeing you at the conference.

Since our last post on Digital Health, FDA has continued their public campaign to raise awareness and seek input on the Software Precertification (Pre-Cert) Program. This blog post covers topics that don’t affect only software companies. While the focus is on software, the potential implications are much broader.  For example, in a recently released document, FDA asked for feedback on the precertification process, from where data could be leveraged so that FDA could adopt a risk-based, streamlined approach to Software as a Medical Device (SaMD) review that could replace the need for a premarket submission or allow for a streamlined premarket review for higher risk products.  Such a program could ultimately affect other 510(k)s as well.

In addition to a draft guidance entitled “Multiple Function Device Products: Policy and Considerations; Draft Guidance for Industry and Food and Drug Administration Staff” which we blogged about here, FDA spoke about Digital Health several times at the Food and Drug Law Institute (FDLI) Annual Conference, held on May 3 and 4, 2018. During one of these sessions, the concept of a streamlined review of software-based medical devices taking 5 – 10 days was floated. FDA acknowledged Digital Health, with its faster, iterative design and development, is not well suited for the current regulatory paradigm. (The same holds true in other areas, such as diagnostic devices using next generation sequencing.) For instance, software-based technologies are regularly updated to fix bugs and provide enhancements to drive further innovation in response to real world performance and user feedback. Unlike most traditional medical device products, Digital Health has the potential to offer real-time learning through real world performance data (e.g., real world health data, user experience data, and product performance data) that can be used to further monitor performance and enable improvements.

Then, on May 10, 2018, FDA held an online interactive user session, led by Associate Director for Digital Health at CDRH, Bakul Patel, to share a program update and answer attendee questions. The session walked through an action plan to align with the 21^st Century Cures Act and discussed a working model of a new regulatory paradigm designed to keep up with the quicker software design cycle. The working model identified the areas FDA is interested in developing through their Pre-Cert program through the challenge questions FDA posed. There are over 50 challenge questions, ranging from specific to the excellence appraisal models and precertification status to review pathway determination, streamlined premarket review process, and real world performance.

FDA correctly recognizes that organizations seeking precertification will have different levels of maturity. Accordingly, FDA is proposing two levels: Level 1 is awarded to an organization who has demonstrated capabilities in all five excellence principles but lacks a record in marketing and maintaining medical devices; Level 2 is awarded to an organization who has both demonstrated excellence and has a demonstrated track record.

The Agency also wants to refine the SaMD International Medical Device Regulators Forum (IMDRF) Risk framework for application in the Pre-Cert Program. This framework is designed to facilitate harmonized risk categorization of SaMD based on intended use where IMDRF type has been introduced as I to IV and subtype is 1 to 9 and is illustrated below:

Based on current thinking, FDA laid out the following table to describe when the precertification of organizations and commitment to leverage real world performance replaces the need for a premarket submission (No Review) or allows for streamlined premarket review (SR), based on the Pre-Cert level of organization: 

Naturally, such a complicated table will present challenges in implementation, but it provides a valuable framework for analyzing the key questions. These coordinated  efforts to share a Multiple Function Device Products draft guidance, working model, challenge questions, and roadmap, in addition to holding in person and online sessions, demonstrate FDA’s commitment to be transparent and build collaboratively. Interested individuals should provide feedback and help drive the next steps for the program either via questions to FDAPre-CertPilot@fda.hhs.gov, comments to the working model, and/or comments to the draft guidance.

* Senior Medical Device Regulation Expert

At long last, the Agricultural Marketing Service (AMS) of the USDA has issued the proposed rule for the National Bioengineered Food Disclosure Standard for food products that have been bioengineered. As readers of this blog know, the Agricultural Marketing Act of 1947 was amended on July 29, 2016 to provide for the establishment of a National Bioengineered Food Disclosure Standard.  Congress gave AMS two years to establish a national standard and the procedures necessary for implementation of the standard.  AMS, however, has had some trouble staying on schedule.  First, the market research required was delayed.  Then, AMS did not publish an ANPR early on, but eventually published questions and asked for feedback.  Now AMS has published a proposed rule a short three months before the deadline that Congress specified for establishing the standard.  Even in the best of circumstances, finalizing a proposed rule in less than three months would be highly optimistic.  And in this instance, it is not the best of circumstances.   The recent proposal raises many questions and undoubtedly will generate many comments.

According to AMS’s summary of the proposed rule, the rule’s purposes are sharing information with consumers and, at the same time, minimizing implementation and compliance costs which would otherwise be passed on to consumers. Some noteworthy aspects of the proposal:

• Terminology: AMS proposes to require the use of the term “bioengineering” (BE) or “BE foods” instead of GMO or genetically engineered foods. Although use of the term BE is consistent with the law, query whether consumers have any idea what BE means. After decades of the use of the term GMO, the introduction of a new term is surprising and may lead to confusion. The first wave of comments to the proposal shows that this may become a contentious issue.
• AMS has punted on the interpretation of “BE food.” In relevant part, the law defines BE as referring to a food that contains genetic material. The question is whether this means that a highly refined food product derived from BE material, but that does not contain genetic material, is a BE food. In response to its questions last year, AMS received comments for two opposing positions, one favoring the interpretation that any food derived from a BE material is subject to a disclosure requirement irrespective of whether it contains genetic material, and one favoring a narrow interpretation limiting the term BE foods to only those food products that contain genetic material. AMS invites comments on the two opposing positions including studies, cost considerations, and which position is more defensible in light of the law.
• Lists of BE commodities: In an effort to make it easier and less burdensome for both industry and consumers to understand what products may need a disclosure statement, AMS proposes a list of highly adopted commercially available BE foods/commodities (canola, field corn, cotton, soybean and sugar beet) and a list of non highly adopted commercially available BE foods/commodities (non-browning cultivars of apples, sweet corn, papaya, potato and summer variety of squash). If other BE foods become available, the list(s) would need to be updated. AMS’s proposal describes the process for updating the lists annually. The lists include commodities, but not all food products derived from those commodities, e.g., it lists corn but not grits, corn syrup, corn flour, etc. However, all foods derived from the listed commodities would be subject to the same disclosure statement as foods on the list. Foods derived from the not highly adopted products could note that the product “may contain” rather than “contains bioengineered ingredients.”
• AMS proposes several options for the BE disclosure statement.
  1. A one-sentence label declaration, such as “contains a bioengineered food ingredient”;
  2. A standardized icon. AMS proposes three alternatives (images and permutations in color and black and white are provided in a separate document). As AMS explains, these icons are designed so they would not disparage biotechnology or suggest BE food is more or less safe than non-BE food.  These standardized icons can be expected to generate comments.
  3. A QR code or other digital marker that directs shoppers to a website for more information, e.g., “Scan here for more food information.” AMS proposes this while acknowledging that it has not yet completed the study on potential challenges associated with electronic disclosures. If AMS were to conclude that electronic disclosure does not provide sufficient access, the agency proposes text message as alternative option.
  4. The proposed rule provides for additional disclosure options for small food manufacturers.
• The 2016 amendment also called on USDA to determine a threshold of bioengineered food present that would necessitate disclosure. The proposed rule includes three different possibilities and invites comments on all three.
• To minimize the burden of recordkeeping, AMS proposes different approaches for regulated entities to keep records that are reasonable and customary to verify the disclosure. For products derived from commodities on the two lists, evidence that the food is derived from the product is sufficient, e.g., for corn tortillas that are labeled with a BE disclosure statement, a record that shows the product is made from corn is sufficient. However, if the label does not disclose that the food is BE or contains a BE food ingredient, then the manufacturer of the retail product would be required to maintain documentation that verifies that the food is not BE.
• AMS enforcement powers are limited. It proposes, in accordance with the law, to perform audits. Companies will have an opportunity to object to the audit findings and request a hearing. Once the audit is final (and challenges have been considered), AMS will publish a summary of the audit findings. The publication of this summary will constitute final agency action. In all likelihood, the real “bite” of a finding of violation would come in the form of follow-on litigation.
• AMS sets Jan. 1, 2020 as the date for compliance for large food companies, and a year later for small companies, defined as those with less than $10 million in annual receipts. These dates coincide with the new compliance dates for the updated nutrition labeling regulations.

Comments may be submitted through July 3, 2018. AMS has indicated that it will not grant an extension because it needs to get the final rule issued as soon as possible.

Last September, we posted on the Fifth Circuit’s decision to uphold summary judgment and award of costs in favor of Solvay Pharmaceuticals, Inc. in a False Claims Act (FCA) case (see post here). The relators pursued an FCA theory against Solvay based on allegations of widespread off-label marketing and violations of the Anti-Kickback Statute.  However, the Fifth Circuit agreed with the district court that relators (the government declined to intervene) had failed to establish, beyond mere speculation, that any alleged kickbacks or off-label marketing caused the submission of a false claim.

Although it appeared in dicta, the Fifth Circuit’s discussion of the FCA’s materiality element in Solvay was of particular interest to us.  The court noted that, if it is true that Medicaid pays for claims “without asking whether the drugs were prescribed for off-label uses or asking for what purpose the drugs were prescribed,” then “given that it is not uncommon for physicians to make off-label prescriptions, we think it unlikely that prescribing off-label is material to Medicaid’s payment decisions under the FCA.”  Slip Op. at 13 n.9.  The Fifth Circuit was not required to reach the materiality element in upholding the lower court’s ruling, because it had already determined that relators failed to establish causation.

Relators filed a petition for writ of certiorari with the Supreme Court, but the Supreme Court declined to hear the case. In their petition, relators raised the Fifth Circuit’s discussion of materiality in off-label promotion FCA cases, claiming that the court’s comments constituted “sabotage of off-label enforcement” that “may well have been intentional.”  Pet. Cert. at 17 n.15.  Asserting that Solvay never raised this issue, relators argued that the court’s comment “suggests hostility to claims based on off-label prescriptions.” Id. Despite the charged rhetoric and accusations, the Supreme Court refused to be persuaded by the specter of a “chilling effect” on relators bringing FCA cases, id. at 17, and the argument will have to wait for another day.  Until then, the Fifth Circuit’s brief analysis of materiality in off-label promotion FCA cases remains a helpful reference for companies facing such claims in a world governed by Escobar’s heightened materiality standard.

FDA announced last week its newest initiative to address alleged “gaming” tactics that FDA believes are used to circumvent the delicate balance of innovation and competition set forth by Congress in the Hatch-Waxman Act.  As part of FDA’s Drug Competition Action Plan, FDA has published a list identifying all drug products for which FDA has received an “RLD access inquiry” related to the limited distribution of the marketed RLD. This list includes the RLD sponsor, the drug product, the number of inquiries received, and any communication from FDA to the sponsor.

In this endeavor, FDA makes public certain information about RLDs for which would-be generic applicants have not been able to obtain samples necessary for generic drug development.  FDA cites failure of the RLD applicant to voluntarily provide such samples as an impediment to patient access to affordable generic alternatives.

In the announcement, FDA explains that it has received inquiries from prospective generic applicants about the limited availability of samples of certain RLDs for generic testing.  Only half of the RLDs listed by FDA are subject of a restricted distribution REMS, the imposition of which makes interstate shipment of the drug much more difficult.  FDA has published guidance indicating that providing the RLD to an interested generic firm would not violate a REMS, and a generic applicant can request a Safety Determination Letter from FDA directly to the sponsor stating this. Products for which a restricted-distribution REMS has not been imposed are not eligible for a Safety Determination Letter; instead, FDA refers the issue to the FTC.

FDA decided to publish this list of RLD access inquiries to provide transparency to the general public about this potential impediment to generic drug market competition. The list includes about 50 different drug products all with at least one RLD access inquiry.  Of note, a number the RLD applicants are themselves generic drug companies.  While Commissioner Gottlieb has denied that this list is an attempt to shame drug companies into providing access, it does appear that, in the absence of any statutory authority, the agency is using “transparency,” publicity, and public reaction to pressure these sponsors to change their practices.

It remains to be seen how effective such a publicity effort will be at addressing this issue. RLD applicants have little incentive to actively aid entities wishing to develop generics of their products regardless of the increased attention to the issue.

All of this said, FDA has no authority to force sponsors to cooperate with their competitors and provide access to their products – and FDA knows that. This exercise shows an FDA willingness to use its bully pulpit to speed up the availability of generic competition.  Only time will tell if this is an effective strategy, but FDA is undoubtedly attempting to be responsive to Congressional pressure regarding pricing concerns and the alleged “gaming” the system discussed in detail at last summer’s public meeting.

On May 16, 2018, Vermont Governor Phil Scott signed Senate Bill 175, which allows for the wholesale importation of prescription drugs from Canada into Vermont.  The new law directs the Vermont Agency of Human Services (VAHS) to design a wholesale prescription drug importation program that complies with federal drug importation laws (21 U.S.C. § 384), including requirements for safety and cost savings.  The program must:

• designate a State agency to either become a licensed drug wholesaler or contract with a licensed drug wholesaler to implement the program;
• use Canadian prescription drug suppliers regulated under the laws of Canada or of one or more Canadian provinces, or both;
• ensure that only prescription drugs meeting the FDA’s safety, effectiveness, and other standards are imported by or on behalf of the State;
• import only those prescription drugs expected to generate substantial savings for Vermont consumers;
• ensure that the program complies with the federal tracking and tracing requirements;
• prohibit the distribution, dispensing, or sale of imported products outside of Vermont’s borders;
• recommend a charge per prescription or another method of support to ensure that the program is funded adequately in a manner that does not jeopardize consumer savings; and
• include a robust audit function.

The chances that a Vermont drug importation program will actually be implemented are modest. Section 804 of the Federal Food, Drug, and Cosmetic Act provides that a program of importation of drugs from foreign countries may become effective only if the Secretary of Health and Human Services (HHS) certifies to Congress that the program will pose no additional risk to public health and safety and will result in a significant reduction in the cost of covered products to the American consumer.  Vermont SB 175 directs the VAHS to submit a formal request for certification of Vermont’s program to HHS by July 1, 2019.  However, HHS has never certified an importation program since the current version of FDC Act § 804 became effective in 2003, and Secretary Alex Azar recently called importation a “gimmick”.  Although Donald Trump advocated importation of drugs from Canada as a way to reduce drug prices during his campaign, he has not mentioned this approach more recently, and his Administration’s recently issued Blueprint to Lower Drug Prices and Reduce Out-of-Pocket Costs did not include it.  Nevertheless, the federal hurdles have not deterred states from pursuing this approach.  Apart from Vermont, at least seven other states are considering foreign importation legislation this year.  Their hope may be to collectively exert pressure on HHS to change its historical views on drug importation.

If other states enact drug importation laws, it will not have been the first time that Vermont has set a trend. In June 2016, Vermont enacted a law requiring drug manufacturers to submit reports to the state justifying their price increases for certain drugs (see our blog post here).  So far, five other states have followed suit with price increase transparency requirements or price limitations (as we reported here and here).  We will continue to monitor and report on the rapidly evolving state landscape on drug pricing, as well as any concrete developments that follow from the Administration’s Blueprint.

We have the technology. It will definitely cost more than six million dollars, and there are questions about whether it will be better than it was before.  But Dr. Sarfaraz Niazi thinks he can rebuild the biosimilar approval process to make it more efficient.

In an interesting Citizen Petition posted last week on regulations.gov, Dr. Niazi provides recommendations to FDA to revamp and expedite the biosimilar approval process. Dr. Niazi, the Forbes-proclaimed “most interesting man revolutionizing the health world” and the man who coined the term “biosimilars,” a professor at the University of Illinois at Chicago and author of multiple bioequivalence textbooks.  In his May 11, 2018 Citizen Petition, he provides a myriad of suggestions for FDA to expedite the biosimilar approval process.

A freestanding petition (i.e. not submitted as a comment on an FDA proposal or a response to a request for information) that was apparently motivated by Commissioner Gottlieb’s speech at the American Health “Insurance Plans’ National Health Policy Conference in March 2018, the Petition addresses a wide range of biosimilar approval issues. Specifically, Dr. Niazi makes five suggestions:

• Allow developers to use of a non-U.S.-licensed comparator product as the reference product without bridging studies;
• Permit substitutions of a biosimilar for an originator product (without an interchangeable designation) for a naive or new patient;
• Agree to the use of in vitro testing to reduce the need for clinical immunogenicity testing;
• Waive certain PK/PD studies of biosimilars; and
• Modify Critical Quality Attribute Tier 1 testing in analytical similarity.

Many of these ideas are not new and reflect some of the comments FDA received on its Draft Guidance Considerations in Demonstrating Interchangeability With a Reference Product. While FDA did not previously make changes in response to these comments, a new administration means new priorities.  Judging from the rapid pace of biosimilar approvals over the last year, this administration is actively trying to increase the number of biosimilars on the market.  Perhaps, given the timing and the increased push for biosimilar approval, FDA may use some of these ideas to hasten the biosimilar approval.

On May 15, FDA issued a Report on the Quality, Safety, and Effectiveness of Servicing of Medical Devices in which FDA concludes that it will not impose additional or different regulatory requirements on the third-party servicers of medical devices at this time.

FDA issued this Report in response to a call from Congress in the Food and Drug Administration Reauthorization Act of 2017 (FDARA). Section 710 of FDARA required FDA to issue a report on the continued quality, safety, and effectiveness of medical device servicing.

The Report begins by stating that “[t]he availability of timely, cost effective, quality maintenance and repair of medical devices is critical” to the U.S. healthcare system. However, the Report explains, some have “expressed concerns about the quality of servicing provided by some third party entities,” such as allegations regarding use of poor quality replacement parts, inadequate training, and failure to restore devices to specifications.

The Report then describes existing authorities and regulations regarding device servicing and FDA’s findings from a 2016 request for public comment and public workshop on this topic. In March 2016, FDA published a Federal Register notice requesting public comment on the topic of refurbishing, reconditioning, rebuilding, remarketing, remanufacturing, and servicing of medical devices performed by third-party entities and original equipment manufacturers (OEMs) (see previous blog post here). The notice did not announce any proposed regulatory scheme; rather, it listed questions designed to gather information from stakeholders on the possible burdens and public health issues related to maintaining or restoring devices to their original or current specifications.  Several months later, FDA announced a public workshop on this topic, which was held in October 2016.

In response to the request for public comment, the Report summarizes, stakeholders identified common elements that influence the quality of activities by medical device service providers, such as the presence of a quality management system, training of the service providers, availability and use of quality replacement parts, and access to device-specific information. At the public workshop, stakeholders provided differing opinions about the servicing performed by OEMs and third-party entities.  OEM stakeholders emphasized the need for mandatory regulatory requirements on third-party entities that provide device servicing, while third-party entities cited a lack of evidence that the current voluntary implementation of quality systems by third-party entities resulted in improper servicing.

The Report also describes FDA’s review of additional evidence regarding medical device servicing from other sources, such as peer-reviewed literature, Medical Device Reports, and complaints and allegations of regulatory misconduct.

The Report states that “[t]he currently available objective information is not sufficient to conclude whether or not there is a widespread public health concern related to servicing, included by third party servicers, of medical devices that would justify imposing additional/different, burdensome regulatory requirements at this time.”

Despite the conclusion not to impose new regulatory requirements related to device servicing, the Report does include plans for some proactive measures by the Agency. In particular, FDA intends to pursue the following actions:

1. Promote the adoption of quality management principles by medical device servicers;
2. Clarify the difference between servicing and remanufacturing;
3. Strengthen cybersecurity practices associated with servicing of medical devices; and
4. Foster evidence development to assess the quality, safety, and effectiveness of medical device servicing.

On the first action, promotion of quality management principles, the Report states that FDA intends to “work with entities performing medical device servicing to identify the essential elements of a voluntary medical device servicing quality framework.” The Report clarifies that FDA does not view this as a “formal regulatory approach mandating adoption” of the Quality System Regulation (QSR).  Though, the Report does not describe how FDA intends to work with entities or whether FDA plans to issue guidance on this issue.

Regarding the second action, clarifying the difference between servicing and remanufacturing, the Report explains that a significant portion of the comments and complaints that FDA received about inadequate device servicing pertain to activities that are more accurately described as device remanufacturing. Because remanufacturing activities, unlike servicing activities, must comply with the QSR, FDA determined that it needs to clarify the difference between servicing and remanufacturing.  FDA intends to publish draft guidance on this topic for public comment.

On the third action, strengthening cybersecurity practices, the Report explains that servicing of devices by third-party entities raises specific cybersecurity challenges related to the third-party entities’ need for privileged access to perform diagnostic, maintenance, and repair functions. The Report states that OEMs, healthcare establishments, and third-party servicers lack the necessary cybersecurity expertise to ensure the “appropriate level of cybersecurity resilience associated with the servicing of medical devices.”  The Report states that the development of standards and best practices could help mitigate cybersecurity risks.  However, the Report does not state how FDA intends to be involved in development of such standards or best practices.

Finally, the fourth action, regarding fostering evidence development to assess medical device servicing, is a response to FDA’s conclusion that the currently available objective evidence is insufficient to conclude whether or not there is a public health concern related to device servicing. The Report states that, because entities engaged in servicing activities have access to relevant information about the quality, safety, and effectiveness of medical device servicing, “any concerted data collection and analysis effort should be a multi-stakeholder enterprise.”  The Report does not contain any concrete plans for a concerted data collection and analysis effort.

The Report concludes by stating that there may be value in creating a public-private forum to address the challenges with delivering quality, safe, and effective servicing of medical devices. FDA states that, if there is sufficient interest and willingness to participate from stakeholders, FDA would facilitate the creation of such a forum.  Considering the active participation by stakeholders in all opportunities to provide public comment to FDA so far, it is likely that stakeholders will pursue FDA’s invitation to shape future regulatory action related to device servicing.

* Law Clerk

On May 15th, FDA published in the Federal Register a proposal to amend the product jurisdiction regulation (21 C.F.R. Part 3). This proposal seeks to update, clarify, and streamline the product classification and designation process.  However, the proposal fails to address some significant flaws in the product jurisdiction and classification decision process.

FDA’s product classification and jurisdiction decisions tend to create conflict between Agency and product sponsors because the costs associated with securing marketing authorization can differ significantly based on a product’s classification. In general, device jurisdiction is favored by manufacturers.

One of the most significant changes proposed by FDA is to remove the regulatory provision suggesting that sponsors should seek reconsideration by the Office of Combination Products (“OCP”) (21 C.F.R. § 3.8(c)) before they can appeal a classification/designation decision to the Office of Special Medical Programs (“OSMP”). FDA correctly points out that reconsideration by OCP itself rarely (if ever) produces a different result, especially in light of the fact that a sponsor is prohibited from providing any additional data for OCP’s consideration.  In its proposal, FDA effectively acknowledges that having already thoroughly reviewed the sponsor’s Request For Designation (“RFD”), nothing the sponsor says in response to OCP will change its mind.  While one can question whether this close-minded approach is the right approach, it does reflect reality.  The removal of this futile step is a welcome change.  It does nothing, though, to address appeals to OSMP, which can languish for many months.  Setting a deadline for OSMP’s decision would be a more valuable step in expediting the process than doing away with reconsideration requests.

Moreover, even with a more streamlined appeal process, the RFD process will not be as efficient as it could be if FDA permitted sponsors to provide more extensive data and reasoning in support of their product classification or designation requests in the first instance. FDA’s proposal retains the current fifteen-page limit, including attachments, for RFDs.  Some of those fifteen pages  are filled by other categories of information required by FDA (such as a detailed description of the product, manufacturing processes, and developmental testing), before a sponsor can get to the business of describing testing to determine the products’ mode(s) of action, comparisons to other products presenting similar issues of safety and effectiveness, etc.  The limitation is also inconsistent with FDA’s views regarding the burden of proof for a classification determination.  The sponsor bears the burden of proving device status, but is constrained in doing so by the fifteen-page limit.  The Agency has previously indicated that a sponsor should prove the absence of chemical action contributing to a therapeutic effect to justify classification as a device.  It is a difficult proposition to prove a negative in less than fifteen pages.  As OCP has asked for ever more data, the fifteen-page limit has become increasingly anachronistic.  FDA should seize the opportunity to drop this unnecessary and arbitrary barrier to providing all the relevant data.

FDA’s proposal also fails to address a more fundamental issue regarding combination products. FDA correctly notes that 21^st Century Cures Act says that a drug/biological primary mode of action “cannot be based solely upon the product having any chemical action.”  However, the Agency goes on to say that this “serve[s] to codify longstanding Agency regulatory interpretation and practices,” and thus warrants no change to the regulation.  In fact, as those who followed the Prevor litigation know, FDA’s actual position has been that a component that exhibits any drug activity that contributes to its therapeutic effect could not be a device.

FDA’s new Part 3 regulation would hold firm – and indeed, further emphasize – that a single “component” of a combination product can have only one “mode of action,” (21 C.F.R. § 3.2) and that mode of action conforms to the component’s statutory definition (i.e. it must be a drug, device, or biologic mode of action).  Thus, for example, if the component exhibits relatively minor chemical action contributing to its therapeutic effect, FDA may determine that it cannot meet the statutory device definition, and therefore cannot exhibit a device mode of action.  Rather, the entire component is deemed to have a “drug” mode of action, even if its action is overwhelmingly physical.  If the purported “drug” component is deemed to contribute most to the therapeutic effect of the combination as a product as a whole, it may then be deemed “primary,” causing the entire combination product to be regulated as a drug by the Center for Drug Evaluation and Research.  FDA’s proposal seems to leave this weighted system in place.

Other proposed changes appear relatively non-controversial, such as FDA’s clarification that a request for “designation” of the Agency component with lead jurisdiction over a product, is also a request for “classification” of the product itself as a drug, device, biologic, or combination product. FDA also proposes to remove excessive verbiage in the regulations definition of a “device mode of action,” which currently reiterates the statutory definition of device, but as revised would simply reference that definition.

Interestingly, in describing the benefits of the changes, FDA alludes “to the value of the illnesses and deaths avoided,” through an improved regulation. FDA hypothesizes that the greater clarity will allow companies to eliminate unnecessary paperwork “and potentially allow sponsors and FDA personnel to divert resources,” to more productive areas.  This seems to us to be something of a stretch.  It is one thing for FDA to say that a clearer product jurisdiction regulation will free up resources for companies, but we would recommend that companies eschew similar speculation in their own marketing applications.

FDA is accepting comments on the new proposed rule until July 16, 2018. This proposal is modestly beneficial, but it represents a lost opportunity to make significant improvements to FDA’s framework and process for product classification and designation decisions.

Last week, the Superior Court of Pennsylvania struck a blow to Appellant Joseph Caltagirone’s wrongful death and survival claims against drug manufacturers Cephalon, Inc. and Teva Pharmaceuticals, USA, Inc. The Superior Court’s non-precedential decision relied on federal preemption principles to affirm the trial court’s dismissal of Appellant’s second amended complaint with prejudice.

Appellant brought wrongful death and survival claims individually and on behalf of his deceased son, who died in 2014 from methadone toxicity. From 2005-2011, a physician prescribed the son Cephalon’s ACTIQ, a fentanyl product approved for treatment of cancer pain of opioid-tolerant patients, to treat his migraines. The product contained an FDA-mandated “Black Box” warning label, advising of serious adverse health risks and specifically warning against the use of ACTIQ for any condition (including migraines) other than cancer pain. The physician nevertheless prescribed the drug for off-label use until moving the son to other opioids.

After his son’s death, Appellant brought suit against Cephalon and its now-parent company Teva, claiming that the companies had engaged in negligence, misrepresentation, fraud, and violation of Pennsylvania’s Unfair Trade Practices and Consumer Protection Law through off-label promotion of ACTIQ. However, the trial court found that the state law claims were “explicitly premised on violation or disregard of [the FDC Act] and FDA regulation,” and that the claims “could not exist in the absence of federal laws and regulations.” Slip Op. at 6. As such, the trial court dismissed the claims as preempted by federal law.

The Superior Court affirmed that decision, explaining the “general rule” that “there is no private right to enforce the law and regulations of the [FDC Act].” Id. at 7 (citing FDC Act § 310(a)). Citing Buckman Co. v. Plaintiffs’ Legal Committee, 531 U.S. 341, 350 (2001) (“State-law fraud-on-the-FDA claims inevitably conflict with the FDA’s responsibility to police fraud consistently with the Administration’s judgment and objectives.”), the Superior Court explained that because Appellant’s claims were based solely on violations of FDA’s off-label restrictions, those claims were preempted by the FDC Act. Id. at 7.

It is important to note that plaintiffs, like Mr. Caltagirone, still maintain the right to bring state law malpractice claims against physicians in such cases. However, the Superior Court’s decision is another holding by a state court that helps to reinforce the shield of federal preemption available to FDA-regulated companies, an issue that is also being debated in current state opioid litigation against drug manufacturers.

The U.S. Food and Drug Administration, in two complaints (here and here) filed last week in federal court, is seeking permanent injunctions to prevent two stem cell clinics from marketing stem cell products without FDA approval.

Specifically, a permanent injunction is being sought against US Stem Cell Clinic LLC of Sunrise, Florida, its Chief Scientific Officer Kristin Comella and its co-owner and managing officer Theodore Gradel for allegedly marketing stem cell products to patients without FDA approval and for allegedly violating current good manufacturing practice requirements, including, according to FDA, some that could impact the sterility of their products, thereby allegedly putting patients at risk.

The FDA is also seeking a permanent injunction to stop California Stem Cell Treatment Center Inc., with locations in Rancho Mirage and Beverly Hills, California; the Cell Surgical Network Corporation of Rancho Mirage, California; and Elliot B. Lander, M.D. and Mark Berman, M.D. personally, from marketing stem cell products to patients without FDA approval. Berman and Lander allegedly control the operations of approximately 100 for-profit affiliate clinics, including the California Stem Cell Treatment Center.

As you may recall, on August 28, 2017, we blogged about the fact that the U.S. Marshals Service, on behalf of FDA, had seized vials of Vaccinia Virus Vaccine (Live) from StemImmune Inc. in San Diego, California. These vaccines were purportedly being administered to cancer patients at the California Stem Cell Treatment Centers in Rancho Mirage and Beverly Hills, California.

According to the FDA press release at the time: “…the vaccine was used to create an unapproved stem cell product (a combination of excess amounts of vaccine and stromal vascular fraction – stem cells derived from body fat), which was then administered to cancer patients with potentially compromised immune systems and for whom the vaccine posed a potential for harm, including myocarditis and pericarditis (inflammation and swelling of the heart and surrounding tissues). The unproven and potentially dangerous treatment was being injected intravenously and directly into patients’ tumors.”

At around the same time as this seizure, the agency had issued a Warning Letter to the U.S. Stem Cell Clinic Inc., LLC, alleging that the autologous stem cells manufactured at this clinic from adipose tissue were more than minimally manipulated and not intended for a homologous use, thereby rendering the products unapproved new drugs, and biologics requiring licensure under 351 of the Public Health Service Act (PHSA). It was alleged that these products were intended by the U.S. Stem Cell Clinic to treat a variety of diseases and conditions, including Parkinson’s disease, amyotrophic lateral sclerosis (ALS), chronic obstructive pulmonary disease (COPD), heart disease, and pulmonary fibrosis. In March of 2017, the clinic was the subject of a New England Journal of Medicine article that stated that three women with age-related macular degeneration were blinded, or had their vision badly impaired, after undergoing procedures at the U.S. Stem Cell Clinic which involved injecting stem cells into their eyes.

At the announcement of the federal complaints seeking these injunctions, FDA Commissioner Scott Gottlieb, M.D. stated that: “[c]ell-based regenerative medicine holds significant medical opportunity, but we’ve also seen some bad actors leverage the scientific promise of this field to peddle unapproved treatments that put patients’ health at risk. In some instances, patients have suffered serious and permanent harm after receiving these unapproved products. In the two cases filed today, the clinics and their leadership have continued to disregard the law and more importantly, patient safety. We cannot allow unproven products that exploit the hope of patients and their loved ones…”

We support sound, scientific research and regulation of cell-based regenerative medicine, and the FDA has advanced a comprehensive policy framework to promote the approval of regenerative medicine products. But at the same time, the FDA will continue to take enforcement actions against clinics that abuse the trust of patients and endanger their health with inadequate manufacturing conditions or by purporting to have treatments that are being manufactured and used in ways that make them drugs under the existing law but have not been proven safe or effective for any use.

After many years of limiting itself to issuing Warning Letters to unlicensed stem cell firms, even when the firms did not heed FDA’s admonitions and continued to treat patients, it is now clear that FDA is willing to take legal action, at least in instances where there appears to be evidence that patients may have been harmed (as with the allegations regarding the U.S. Stem Cell Clinic), or may imminently be harmed (as with the allegations regarding California Stem Cell Treatment Center).

Notwithstanding a statutory deadline of two years after the enactment of the 2013 Drug Supply Chain Security Act (“DSCSA”), FDA has finally published a draft guidance document on waivers, exceptions, and exemptions (“WEE”) from certain requirements of FDCA Section 582.  Since late November 2013, the pharmaceutical drug supply chain and FDA have been inching towards implementation of the DSCSA’s multi-layered requirements aimed at enhancing drug supply chain security.  Pursuant to Section 582, trading partners in the pharmaceutical distribution supply chain must implement over a period of time certain tracking, tracing, and product identification requirements.  Section 582(a)(3) contains a “waiver, exception, and exemption” provision permitting under certain circumstances trading partners to apply to FDA for a WEE from what can be onerous compliance provisions (and FDA can initiate waivers and exemptions on its own).  Although lacking in much detail on what types of products or under what conditions trading partners may receive the requested WEEs, at least there is a process in place to attempt to obtain one before the effective date of FDA’s product identification (i.e., serialization) requirements go into effect later this year.

The short draft guidance document describes generally that WEE requests should be in writing (either paper or electronic), and submitted by a trading partner or stakeholder to the product correspondence file associated with the particular application for CBER-regulated products. For all other WEE requests, including CDER-regulated products, such requests should be submitted to CDER as set forth in the draft guidance. (An appendix to the guidance contains FDA contact information for submissions.)

The draft guidance details what a requester should include in each WEE request:

• The name, telephone number, and email address of an individual who FDA can contact about matters relating to the proposed waiver, exception, or exemption
• The identity of the trading partner(s) that would be covered by the proposed waiver, exception, or exemption
• A description of the activities and/or products (including the national drug code number) for which the proposed waiver, exception, or exemption is being sought
• The requested effective period of the waiver, exception, or exemption
• The requirements of FDC Act Section 582 to which the proposed waiver, exception, or exemption would apply
• A detailed statement of the reasons why FDA should grant the proposed waiver, exception, or exemption, including pertinent supporting documentation

FDA will also require the applicant to complete an attestation concerning the veracity of the information pursuant to 18 U. S.C. § 1001. FDA states that it will review the requests, and determine whether the request is sufficient.   Along with considering risks to the security of the supply chain, the Agency will review a request with its subject matter experts, and determine as follows:

• Whether a waiver request concerning the Section 582 requirements identified in the request is warranted because compliance with it would result in undue economic hardship or is appropriate with emergency medical reasons.
• Whether a request for an exception to Section 582’s requirements relating to product identifier is warranted because the product package is too small or otherwise unable to accommodate a label with sufficient space to hold all the required information
• Exempting products and/or transactions identified in the request from Section 582 requirements is appropriate to maintain public health “or is otherwise appropriate.”

Furthermore, FDA states that the Agency may initiate its own WEE, or may grant a request of limited duration. To minimize risks to the supply chain, FDA expects to limit the duration of WEEs that it grants. FDA will notify requesters in writing of its determinations and may post such information on its website as well, consistent with laws concerning disclosure of such information.

FDA expects to review or reevaluate requests biennially. It will renew such WEEs “as applicable” and determine whether there has been a material change in circumstances affecting the necessity of the WEE. FDA specifically notes as an example of requesting additional information: a situation where a recipient received an “undue economic hardship” waiver may be asked to submit financial information so FDA may determine whether financial circumstances changed.

With respect to “material changes” after a request is granted (i.e., an increase in package size such that the package would be able to accommodate a product identifier), FDA expects the requestor to notify FDA of the material change, and not await FDA’s biennial review of the request. FDA also describes its proposed process for FDA-initiated exceptions and exemptions, stating it only intends to use these as necessary when an issue affects broad segments of a product market (i.e., a drug container is too small or unable to accommodate a label to bear information required under the DSCSA). These situations will seemingly be rare, as FDA states it will only initiate such exceptions and exceptions when necessary to protect the public health.

Late last month, CDER’s Office of Pharmaceutical Quality (OPQ) published a MAPP (Manual of Policies and Procedures #5310.3) outlining its policy for granting or denying expedited reviews of NDA and BLA Prior Approval Supplements (PAS) that involve chemistry, manufacturing and controls (CMC) changes overseen by OPQ.

Below are the pertinent highlights of the MAPP:

• An expedited review in the context of this MAPP, is FDA-speak for seeking to assess and act on the PAS prior to the Prescription Drug User Fee Act (PDUFA) goal date associated with that PAS;
• Normally, the sponsor is expected to make the request for expedited review, however, if the public need arises, OPQ may designate the CMC PAS for expedited review of its own initiative;
• OPQ will only consider requests for expedited review that clearly state the basis for the request;
• OPQ can designate a CMC PAS for expedited review at the time it receives the PAS or at any time thereafter. For instance, if OPQ receives a request for expedited review after the office has already processed the PAS, OPQ will consider the request and could still expedite the review of the PAS;
• OPQ will not consider a request for an expedited review that involves a facility that is subject to an OAI recommendation, unless an expedited review will help address a public health concern;
• OPQ will consider an expedited review request for a CMC PAS that falls into one of the following categories:
  • drug shortages;
  • special review programs such as the President’s Emergency Plan for AIDS Relief;
  • public health emergencies;
  • certain government purchasing programs;
  • statutory mandates or other legal requirements;
  • events that constitute extraordinary hardship on the applicant, such as a catastrophic event (eg, storm or fire damage), or the discontinuation of supply of an active ingredient or other material.

As it turns out, the categories for which OPQ will consider an expedited review request for a CMC PAS are not that dissimilar from the ones that the Office of Generic Drugs has previously indicated it will consider for expedited review of ANDAs, ANDA amendments, and ANDA supplements in its MAPP 5240.3, the most recent version of which was published on November 9, 2017. The only difference between the two MAPPs in that regard is that MAPP 5240.3 also includes the following categories, which are a function of the types of applications it reviews:

• submissions containing certain patent certifications and exclusivity statements;
• submissions for “sole source” drug products, i.e., “Submissions for drug products for which there is only one approved drug product listed in the Prescription Drug Product List (i.e., the “active section”) of the Orange Book and for which there are no blocking patents or exclusivities may receive a priority review, except when the approved drug product was approved pursuant to a suitability petition under section 505(j)(2)(C) of the Federal Food, Drug and Cosmetic Act.”

To summarize, the new MAPP 5310.3 for CMC PASs related to NDAs and BLAs is just a logical extension of the pre-existing MAPP 5240.3 for ANDAs, ANDA amendments and ANDA supplements. So, the next time your API supplier’s facility is knocked out by a torrential storm, you’ll know FDA’s position regarding the expedited review of your application or supplement!

On April 27, 2018 FDA released a draft guidance describing the regulatory approach and policy for multiple function device products. The draft guidance, Multiple Function Device Products: Policy and Considerations, is available here and has been issued in response to the 21st Century Cures Act section 3060(a) “Clarifying Medical Software Regulation.”

The term “function” is defined as “a distinct purpose of the product, which could be the intended use or a subset of the intended use of the product.” Draft Guidance at 4. The draft guidance is intended to clarify how FDA assesses the impact of functions that are not subject to FDA review when they are part of a multi-function product that includes at least one function that is subject to FDA review.

In short, the draft guidance indicates that FDA will not regulate functions of a multi-function product that do not meet the statutory device definition or are devices that are subject to an existing enforcement discretion policy. Also, though issued in relation to software functions, FDA states that they apply the same principles to the assessment of all multiple function products, not just those that contain software.

During review of premarket applications, FDA will assess the impact of “other functions” on a device function-under-review without reviewing the specifics of the other functions’ design and performance not related to the device function-under-review. In assessing the impact that these other functions may have on the device function-under-review, FDA will consider whether the other function(s) may impact the safety or effectiveness of the device function-under-review, by considering “whether there are shared computational resources, data dependencies, or any other type of relationship between the functions.” Id. at 9. If the other function(s) may impact the safety or effectiveness of the device function-under-review, FDA will consider whether there is an increased risk or adverse effect on performance.

Although sponsors may include information on other functions that positively impact the device function-under-review in their premarket submissions, FDA will only look for documentation on other functions in cases where the other function “could adversely impact the device function-under-review.” Id. at 11. A premarket submission for a multi-function device that includes other functions that could adversely impact the device function-under-review should include a description of the function, architecture and design information, risk analysis, requirements, and specifications. Also, FDA intends to include language in the submission summary (e.g., 510(k) summary) to indicate that “FDA assessed functions not subject to premarket review only insofar as they might adversely impact the safety and effectiveness of the functions subject to FDA premarket review.” Id. at 12.

This draft guidance should help those developing multiple function products to better understand how to limit their submissions to data and documentation for other functions only when they could adversely impact the device function-under-review. The boundaries have not always been clear in the past.

On the postmarket side, general control requirements are not applicable to non-device functions and will not be enforced for functions for which FDA does not intend to enforce applicable regulatory controls.

This area of device regulation has always been somewhat murky. The draft guidance is a positive step forward in providing clarity, even if it does not break new ground.